Ambient air pollution at concentrations below the limits set by current regulatory standards is associated with significant adverse effects on children's respiratory health. A growing number of studies demonstrate that particulate matter (PM) and traffic-related near-roadway air pollutants (NRP) have substantial adverse health impacts, and that asthma and epigenetic or genetic sequence variants may increase susceptibility for air pollution-associated deficits in lung growth, bronchitis symptoms, and development and/or exacerbation of asthma. Intensive public health and regulatory interventions have reduced current levels of PM, ozone and NO2. It is unknown whether the reduced levels of the current ambient air pollution mixture are sufficient to protect children's health. Improved approaches for early detection of these chronic effects at the population level are needed to guide effective public health and regulatory interventions and to assure that children are fully protected from long-term adverse effects due to these air pollution exposures. One promising approach for population-based early detection is the use of exhaled nitric oxide (FeNO). FeNO50 is associated with acute adverse respiratory effects and is modulated by short-term acute changes in air pollution exposure. Furthermore, the proximal and distal airways may be focal points for adverse chronic effects of PM2.5, and NRP. We have developed new methods to characterize responses in the proximal and distal airway compartments using extended exhaled nitric oxide parameters [proximal bronchial wall flux (J'awNO), distal alveolar NO concentration (CANO)]. In this application, we propose to investigate the utility of FeNO for detecting the early effects of chronic exposures to air pollution, using data on long-term air pollution, FeNO, epigenetic and genetic variants in NOS2, and health outcomes measured longitudinally in the southern California Children's Health Study, an ongoing prospective population-based cohort study of environmental determinants of respiratory health in southern California children. Over 7 years of follow-up, which coincided with substantial reductions in levels of air pollution in southern California, we have collected more than 13,000 longitudinal measurements of FeNO50. We hypothesize that 1) FeNO50 and CANO can be used for early detection of chronic health effects from long-term exposure to PM2.5 and elemental carbon, EC2.5 (a measure of NRP); and 2) that early detection of chronic effects can be enhanced using epigenetic (DNA CpG methylation) and cis genetic sequence variants in NOS2 that are synergistically associated with both acute and chronic differences in FeNO50, J'awNO, CANO, and increased susceptibility to EC2.5 and PM2.5. The results from this program of research will fill crucial gaps in our ability to rapidly identify chronic effects of air pollution in the periodbefore irreversible adverse respiratory effects occur.